Acometimento vascular na doença de Behçet: o processo imunopatológico / Vascular involvement in Behçet's disease: the immunopathological process

Resumo A doença de Behçet constitui uma forma rara de vasculite sistêmica, que acomete de pequenos a grandes vasos. É caracterizada por manifestações mucocutâneas, pulmonares, cardiovasculares, gastrointestinais e neurológicas. Sua apresentação clínica é bastante ampla, variando de casos mais brandos a casos graves, com acometimento multissistêmico, caracteristicamente com exacerbações e remissões. Suas causas ainda são desconhecidas; entretanto, há evidências genéticas, ambientais e imunológicas, como a associação com o alelo HLA-B51. Todas essas, em conjunto, apontam para um processo imunopatológico anormal, com ativação de células da imunidade inata e adaptativa, como as células natural killer, neutrófilos e células T, que geram padrões de respostas e citocinas específicos capazes de gerar mediadores que podem lesionar e inflamar o sistema vascular, resultando em oclusões venosas, arteriais e/ou formação de aneurismas.

Abstract Behçet's disease is a rare form of systemic vasculitis that affects small to large vessels. It is characterized by mucocutaneous, pulmonary, cardiovascular, gastrointestinal, and neurological manifestations. Its clinical presentation is quite wide, ranging from milder cases to severe cases, with multisystemic involvement, characteristically with exacerbations and remissions. Its etiopathogenesis is still unclear, although there is evidence of genetic, environmental, and immunological factors, such as the association with the HLA-B51 allele. In conjunction, all of these point to an abnormal immunopathological process, with activation of cells of innate and adaptive immunity, such as NK cells, neutrophils, and T cells, which generate specific response patterns and cytokines capable of generating mediators that can damage and inflame blood vessels, resulting in venous and arterial occlusions and/or aneurysm formation.

Clinical phenotypes of Korean patients with Behcet disease according to gender, age at onset, and HLA-B51

BACKGROUND/AIMS: The clinical manifestations of Behcet disease (BD) have been reported to differ according to country, region, and race. Gender, onset age, and human leukocyte antigen (HLA)-B51 have also been known as the factors that influence the clinical features of BD. The aim of this study is to investigate the clinical phenotypes of Korean patients who visited the rheumatology clinic with BD with respect to gender, onset age, and HLA-B51. METHODS: Total 193 Korean patients (129 females and 64 males) fulfilling the international criteria for BD were retrospectively assessed. RESULTS: The mean age at disease onset and disease duration of the BD patients were 32.2 ± 11.1 and 14.2 ± 9.3 years, retrospectively. Females suffered more frequently from genital ulcers (90.7% vs. 75.0%, p 40 years) suffered from neurologic involvement (15.9% vs. 4.2%, p = 0.007) more frequently than those with early onset of BD. The patients with HLA-B51 showed earlier onset of disease than without HLA-B51 (28.3 ± 11.4 years vs. 33.8±11.6 years, p = 0.02) and the neurologic and gastrointestinal involvements were more frequent in the patients without HLA-B51 than with HLA-B51 (17.2% vs. 2.5%, p = 0.02 and 20.7% vs. 2.5%, p = 0.01, respectively). CONCLUSIONS: The clinical phenotypes in Korean patients with BD may be influenced by gender, onset age and HLA-B51.

Doença de Behçet ocular: a nossa realidade / Behçet disease: our experience

Resumo Objetivo: A doença de Behçet é uma vasculite inflamatória sistémica, de etiologia desconhecida. Pode atingir virtualmente todos os sistemas, sendo as manifestações oculares comuns. O objectivo deste trabalho foi analisar doentes com doença de Behçet ocular quanto aos parâmetros demográficos, manifestações clinicas, terapêutica e principais complicações. Métodos: Estudo descritivo e retrospetivo, que incluiu 11 doentes com o diagnóstico de doença de Behçet ocular, segundo os critérios do ISG, observados na consulta de Inflamação Ocular do Hospital Prof. Doutor Fernando da Fonseca nos últimos 3 anos. Resultados: Identificaram-se 11 doentes, 5 homens e 6 mulheres, todos caucasianos. A idade média ao diagnóstico foi de 33,45±6,49 anos. A manifestação ocular foi o primeiro sinal da doença em 2 doentes. Em 72,7% dos casos as manifestações oculares foram bilaterais. Identificaram-se 4 casos de panuveíte, 3 de uveíte posterior, 2 de uveíte anterior, 1 de queratite e 1 caso de episclerite. O glaucoma e a catarata foram a complicação ocular mais frequente. O tratamento sistémico incluiu a corticoterapia oral em associação com terapêutica adjuvante imunossupressora, sendo os mais utilizados a azatioprina e a ciclosporina. Em 3 doentes houve necessidade de terapêutica biológica com infliximab para controlo da doença. Conclusão: A manifestação ocular mais frequente foi a panuveíte. Esta doença pode condicionar complicações oculares com diminuição irreversível da acuidade visual. A orientação destes doentes exige uma abordagem global e interdisciplinar.

Abstract Objective: Behçet's disease is a systemic inflammatory vasculitis of unknown etiology. It can virtually reach all systems, being common ocular manifestations. The aim of this study was to analyze patients with ocular Behcet's disease regarding demographic parameters, clinical manifestations, therapeutic approach and main complications. Methods: Descriptive and retrospective study, including 11 patients diagnosed with ocular Behcet's disease, according to the ISG criteria, observed in the Ocular Inflammation appointment of the Hospital Prof. Doutor Fernando da Fonseca in the last 3 years. Results: We identified 11 patients, 5 males and 6 females, all caucasian. The mean age at diagnosis was 33.45 ± 6.49 years. Ocular manifestation was the first sign of the disease in 2 patients. In 72.7% of the cases, ocular manifestations were bilateral. There were four cases of panuveitis, 3 of posterior uveitis, 2 of anterior uveitis, 1 of keratitis and 1 case of episcleritis. Glaucoma and cataract were the most frequent ocular complications. Systemic treatment included oral corticosteroid therapy in combination with adjuvant immunosuppressive therapy, and the most commonly used was azathioprine and cyclosporine. In 3 patients there was a need for biological treatment with infliximab to control the disease. Conclusion: The most frequent ocular manifestation was panuveitis. This disease can promote eye complications with an irreversible decrease in visual acuity. Orientation of these patients requires a global and interdisciplinary approach.

Behçet's disease with multiple splenic abscesses in a child

We report the case of a 5-year-old male patient with multiple aseptic splenic abscesses associated with Behçet's disease. The patient visited Gachon University Gil Hospital with fever, abdominal pain, and acute watery and bloody diarrhea, and reported a 2-year history of chronic abdominal pain and intermittent watery diarrhea. He was treated with antibiotics at a local clinic for fever and cervical lymph node swelling. Additionally, he had recurrent stomatitis. A colonoscopy showed multiple well-demarcated ulcerations throughout the colon, and abdominal computed tomography showed multiple splenic abscesses. Pathergy and HLA-B51 tests were positive. Investigations did not reveal any infectious organisms in the aspirate obtained via ultrasound-guided fine needle aspiration. After steroid treatment, all symptoms and multiple aseptic splenic abscesses resolved. However, oral ulcers, genital ulcers, and abdominal pain recurred after tapering the steroids. Infliximab treatment improved the patient's symptoms. However, 5 months after the treatment, the symptoms recurred. The treatment was changed to include adalimumab. Subsequently, the patient's symptoms resolved and colonoscopic findings improved. No recurrence was noted after 3 months of follow-up.

The association between smoking and clinical manifestations in patients with Behcet's disease / 대한내과학회지

BACKGROUND/AIMS: There is controversy related to the role of smoking in affecting the clinical features of patients with Behcet's disease (BD). The aim of this study was to investigate the effect of smoking on clinical manifestations in Korean BD patients. METHODS: We enrolled 131 patients with BD who fulfilled the International Study Group (ISG) criteria of 1990. The disease-related clinical features of BD-oral ulcers, genital ulcers, ocular lesions, arthritis, vascular lesions, gastrointestinal lesions-and central nerve lesions, smoking history, disease duration, and the presence of HLA-B51 were retrospectively assessed through medical record reviews and patient interviews. Statistical analysis was performed using Chi-square, Fisher's exact, or student t-test, if appropriate. RESULTS: The frequencies of vascular and gastrointestinal lesions in smokers were significantly increased compared to those in non-smokers (p=0.040, OR=3.341, 95% CI 1.083-10.305; p=0.012, OR=3.878, 95% CI 1.379-10.906, respectively). Male smokers developed vascular lesions more frequently compared to female smokers, male non-smokers, and female non-smokers (p=0.025, OR=3.896, 95% CI 1.245-12.196). Moreover, smoking, male sex, and positive HLA-B51 may be risk factors for the development of gastrointestinal lesions in BD. Venous lesions were more frequently found in male smokers compared with other patients (p=0.038). CONCLUSIONS: Smoking may be associated with the development of vascular and gastrointestinal lesions in Korean BD patients. A large population prospective assessment of the clinical effect of smoking on BD is needed.

Behcet's Disease Presenting with Clinical Manifestations of Moyamoya Disease / 대한류마티스학회지

Central nervous system involvement of Behcet's disease (BD) shows various neuropsychiatric manifestations. The differential diagnosis may include many other systemic or neurologic diseases. Moyamoya disease (MD) is a progressive cerebrovascular occlusive disease of unknown etiology with a high incidence in Korea and Japan. HLA-B51 is significantly associated with both MD and BD. We first report a case of BD associated with MD in a 32-year-old woman with transient ischemic attacks of left hemiparesis and episodic dizziness. She was diagnosed as having BD manifested with oral ulcer, genital ulcer, erythema nodosum and positivity of pathergy reaction and HLA-B51. There was no evidence of cerebral infarction or hemorrhage in brain MRI. MR angiogram and 4-vessel angiography showed occlusion of bilateral internal carotid arteries and the development of collateral circulation, suggestive of MD. Bypass surgery was successfully performed. When evaluating the manifestations of MD, a chronic inflammatory disease, such as BD, needs to be considered as the underlying disease, especially in prevalent area of both diseases.

New Insights on the Pathogenesis of Behcet's Disease / 대한류마티스학회지

Behcet's disease (BD) is a chronic inflammatory disorder of unknown cause, characterized by recurrent oral ulcerations, genital ulcerations, ocular and skin lesions. Although the exact pathogenesis for BD is not completely understood, it has been suggested that the disease is triggered in genetically susceptible individuals by environmental factors, such as microbial agents. It is noted that multiple genes, including MHC and non-MHC genes, are implicated in the pathogenesis of BD. Although the HLA-B51 is known to be the candidate gene showing the strongest association with BD, it is necessary to be determined whether this HLA molecule is directly involved in the pathogenesis of BD. Cross-reactivity between microbial 65-kD and human 60-kD heat shock proteins is demonstrated to cause an increased T cell (particularly gammadelta T cell) response. The resultant overexpression of pro-inflammatory cytokines (mainly Th-1 type) from several immune cells seems to be responsible for the enhanced inflammatory reaction, and this may be associated with the genetic factors.

The study of HLA antigens in a familial Behcet? disease / 대한류마티스학회지

OBJECTIVE: Behcet? disease (BD) is a chronic inflammatory disorder affecting several organs. The etiology of BD remains unclear, although genetic factors, infectious agents, and immune mechanisms have been studied. The association of BD with certain genetic factors, especially HLA-B51 antigen, is well known in some geographical areas. Nevertheless, the familial occurrence of BD is rare. In this paper, HLA phenotype was evaluated in one family member showing the clustering of BD. METHODS: The serological tissue typing of HLA class I and class II antigens was performed by standard National Institutes of Health microlymphocytotoxicity method in seven family members in which four siblings were affected by BD. The diagnosis of BD was established by the criteria of the International Study Group of BD in these four siblings. RESULTS: In this family study, all members had HLA-A2 and DQ3 antigens. Although HLA-B51 antigen was positive in six out of seven family members, BD was developed in three of the six having HLA-B51 antigen. Three siblings had the exact same HLA phenotype. However, only one person had BD among three siblings with identical HLA phenotype. In addition, all siblings who developed erythema nodosum-like lesion had HLA-B51 antigen. CONCLUSION: This family suggests that the familial clustering of BD may not be explained solely by a susceptible HLA phenotype. The environmental factor or other genetic factors besides HLA-B51 might play a role in the development of BD. Furthermore, more studies and information will be needed to clarify the role of A2 and DQ3 antigens in BD.

The Frequencies of HLA Alleles in Bipolar Disorder / 신경정신의학

OBJECTIVES: To evaluate the potential of HLA as a candidate gene for the genetic marker of bipolar disorder, we carried out the association study between allelic frequency of HLA and bipolar disorder. METHODS: HLA class I and class II allelic frequencies were assessed in 87 Korean bipolar disorder patients and were compared with the data from 206 normal controls. HLA class I typing was performed with microlymphocytotoxicity method and HLA class II(DQB1 and DRB1) genotyping with reverse dot hybridization. The allelic frequencies were analyzed using x2 test with two-tailed Fisher's exact test. RESULTS: Bipolar disorder patients showed increased allelic frequencies of HLA-A29 and B54 and decreased allelic frequencies of HLA-B51 and DRB1*02 compared to normal controls. CONCLUSION: These results suggest the possibility of association between HLA gene and bipolar disorder. To clarify the genetic influences of HLA on bipolar disorder, further systematic studies should be conducted.

Analysis of Typing in Patients with Uveitis in Korean Population

In order to evaluate association of particular HLA typing with certain uveitis in Korean population, HLA antigens were analyzed in 114 uneitis patients(acute anterior uveitis: 32 cases, Behcet`s disease: 25 cases, intermediate uveitis: 19 cases, Vogt-Koyanagi-Harada (V-K-H) syndrome: 10 cases, retinal vasculitis: 12 cases, Eale`s disease: 3 cases, posterior uveitis: 9 cases, pan.uveitis: 4 cases). The stronger association between acute anterior uveitis and HLA-B27 was statistically significant, and this result was similar to reports in other ethnic groups. Also, the association between V-K-H syndrome and HLA-DR4 showed same results. But the high frequency of HLA-DR7 in the patients with V-K-H syndrome was unque in patients of Korean popjlation and statistically significant. The association between HLA-A2 and posterior uveitis was high in patients of Korean population and statistically significant. Behcet`s disease was stronger association with HLA-B51 but not statistically significant and much weaker association than reports in Japanese group. Although many similarities of associations between particular uveitis and HLA typing were detected as compared with other ethnic groups, distinctive HLA associations were demonstrated in Korean population. Additional cases and long-term follow-up are required to confirm the association with HLA typing and the relationship with prognosis including clinical and laboratory variabilities.

Prognostic comparison of Behcet's disease with or without HLA-Bw 51 antigen

To know the prognosis of Behcet's disease with HLA-Bw 51 antigen, comparison studies of 24 cases of Behcet's disease were investigated. The sex distribution was 14 males (58%) and 10 females (42%). The patients were grouped into three clinical types: the complete type with 11 cases (45%), the incomplete type with eight cases (33%) and the suspect type with five cases (22%), according to the criteria established by the Behcet's Disease Research Committee in Japan (1982). They were also divided into three ocular types according to the location of the inflammation: the anterior segment type, the fundus type and the mixed type. They were divided into 10%, 10% and 60% in HLA-Bw 51 negative group and 14%, 22% and 64% in HLA-Bw 51 positive group, respectively. Skin lesions observed in 30% of the HLA-Bw 51 negative group and 70% of the HLA-Bw 51 positive group, which was statistically significant (p 0.1).